Reactivity to stress is insidious because it does not directly incapacitate a human. Researchers are discovering that stress decreases productivity, and eventually may lead to illness. As mentioned above, this reactivity to stress can be brought about by the daily hassles--the repeated or chronic strains of everyday life. Research in this area has shown that the daily hassle, as measured by self-report, is more strongly associated with somatic health than are life event scores. That is, the frequency and intensity of hassles are significantly related to somatic illness (A. Delongis, et al, Health Psychology, 1981, 1 (2), 119-136).
Chronic reactivity, as measured by elevated blood pressure, particularly systolic blood pressure, is correlated with disease. By use of a portable blood pressure-measuring device, it has been shown that regularly recurring stress (specifically that occurring in the work place) correlates with the occurrence of left ventricular hypertrophy. In particular, it was shown that the correlation exists in patients showing elevated systolic blood pressures while actually engaged in their workday tasks (R. B. Devereux, et al, Circulation 68, No. 3, 470-476, 1983). In another study, blood pressures measured every 15 minutes for 24 hours in 25 normal subjects, 25 borderline subjects and 25 established hypertensive subjects showed significantly higher blood pressures at work than at home, at the physician's office or while sleeping. (T. G. Pickering, et al, Clinical and Experimental Hypertension, A4(4&5), 675-693 [1982]).
The classical techniques used for controlling reactivity to stress include biofeedback, meditation and drugs.
With respect to biofeedback, Benson, et al, cited infra, used the constant-cuff technique and gave feedback and reinforcement for the lowering of systolic blood pressure in seven patients, five of whom had been diagnosed as having essential hypertension. The five patients with hypertension responded positively, all showing significant decreases in their systolic blood pressures after 30 sessions of training (Benson, H., Shapiro, D., Tursky, B., and Schwartz, G. E., Science, 1971, 173, 740-742).
Other physiological parameters used for biofeedback training include pulse transit time, electromyogram activity and skin resistance biofeedback.
The type of relaxation training techniques used for the treatment of hypertension are variations of either certain Eastern meditative disciplines, progressive relaxation techniques or autogenic training. These techniques are intended to lower blood pressure by promoting physical and mental relaxation. For example, the Benson relaxation response technique (Benson H., et al, Psychiatry 1974, 37, 37-46) was used to lower the blood pressures of 22 untreated borderline hypertensive patients and 14 pharmacologically-treated hypertensives. Mean blood pressure during a 6-week baseline was 147/95 mm/Hg for the untreated patients and 146/ 92 for the treated patients. After 25 weeks of meditation-relaxation, blood pressure reductions of 8/4 mm/Hg and 11/5 mm/Hg were reported for the untreated and treated patients, respectively. A review of the use of biofeedback and relaxation techniques for the treatment of hypertension can be found in: Surwit, et al, "Behavioral Approaches to Cardiovascular Disease", Behavorial Medicine Series, Academic Press, 1982, 139-156.
Man has also sought chemical agents to modify the effects of stress, tension, anxiety and dysphoria throughout recorded history. Probably, the oldest drug for this use is ethanol. In the last century, bromide salts and the barbiturates were introduced. Barbiturates continued to be the dominant anti-anxiety agents , until the 1950's when propandiol carbamates (MEPROBAMATE.RTM.), and congeners were introduced. The side effects of the barbiurates and the propandiol carbamates, in particular, the physical dependence caused by these drugs and the severe accute intoxication on overdosage, encouraged the search for more specific anti-anxiety drugs. Chlordiazepoxide (LIBRITABS.RTM.) was discover in the late 1950's followed by chlordiazepoxide hydrochloride (LIBRIUM.RTM.), diazepam (VALIU.RTM.), Lorazepam (ATRIV.RTM.) and some dozen other benzodiazepine congeners. Today the benzodiazepines series of drugs, chlordiazepoxide and diazepam in particular, are the major drugs used for treatment of anxiety and stress. A review of the drug treatment of stress and anxiety can be found in: Goodman and Gilman, "Pharmacological Basis of Therapeutics", 6th ed., MacMillan Publishing Co., New York, N.Y., (1980), pages 436-446.
The current pharmacologic treatment of hypertension is based on the "stepped-care" approach. When blood pressure remains above 140/90 mm/Hg., the first step is to place the patient on a thiazide diuretic. If the diuretic does not achieve reduction off blood pressure, the next step is to add a centrally-acting sympatholytic agent (e.g., Methyldopa) or a .beta.-andrenergic blocking agent (e.g., propranolol). If the second step does not result in normalization of blood pressure, the third step is to add a direct-action vasodilator (e.g., hydralazine). If the third step does not work, a variety of other agents must be devised on a individualized basis for each patient (Surwit, R. S., et al, "Behavioral Approaches to Cardiovascular Disease", Academic press, New York, page 138, [1982]).
Our invention for the reduction of physiological and/or subjective reactivity to stress differs from the drug approach both in dose level and concept. The dose levels (presented hereinafter) are much lower than those used for the drug therapies presented above (microgram levels vs. milligram levels). The concepts differ in that our invention is for the prevention of surges in systolic blood pressure rather than a cure for a sickness. Unlike biofeedback or meditation, our invention does not require training sessions. However, meditation, like our invention, can be used to control physiological and/or subjective reactivity to stress.
Our invention for stress reactivity reduction utilizes plant-derived substances common to the fields of perfumery and aromatherapy. The dose levels, however, differ from those normally employed in either perfumery or aromatherapy and the mode of application differs from those normally employed for aromatherapy and are significantly less. In addition, concern over (minor) blood pressure surges and possibilities for damping such surges appear to be absent in the folk medicine literature.
The term "Aromatherapy" is intended herein to mean the use of plant-derived substances; volatile substances derived from plants for the treatment of health problems. Generally, the volatile fraction--the essential oil fraction--of the plant-derived substance is used. The use of the volatile fractions of plants for treatment of various ailments is reviewed in the following three monographs:
A detailed analysis of the aromatherapy folk medicine literature suggested that a number of essential oils commonly used in perfumery might have a multiplicity of medical effects. Some of these oils are employed in the practice of this invention.
Neroli oil is the essential oil obtained from orange blossoms. Neroli oil has a folk medicine history as being an anti-depressant, aphrodisiac, antiseptic, antispasmodic and of having digestive and sedative activity. The anecdotal literature suggests that neroli oil is an effective sedative and anti-depressant and that it may be used for insomnia, hysteria, states of anxiety and depression (R. Tisserand, "The Art of Aromatherapy", cited, supra). Tisserand further states:
"Neroli is one of the most effective sedative-antidepressant oils: it may be used for insomnia, hysteria, states of anxiety and depression. It calms and slows down the mind. It also has a notable action on the heart, diminishing the amplitude of heart muscle contraction, hence its use in palpitations or other types of cardiac spasm. Derived from this is its use in panicky, hysterial, fearful types of people--those who upset themselves unnecessarily, and become over wrought over nothing. One can also see that neroli is a valuable remedy for shock, or for disorders caused by sudden shock, or fear, causing a strain on the heart. It is valuable in chronic diarrhoea, when this is related to long-standing stress or fear. Its action is slow but sure. PA0 Oil of neroli also has a pronounced action on the skin. Like lavender and geranium it can be used with benefit on any type of skin. It is totally non-irritant and may be used where there is irritation or redness. It is said to be useful for dry skin and broken veins. It is one of the oils which acts on a cellular level stimulating the elimination of old cells and the growth of new ones. Neroli makes a luxurious, relaxing, and deodorant bath oil. PA0 Orange-flower water is soothing, digestive, carminative. It makes a very useful, mild remedy for infants' colic, and its sedative action helps to send them to sleep." PA0 "Russian Experience: Valeriana is known to Folk Medicine as having a general calming and sedative effect on the central nervous system, to induce sleep and rest, spasms of the stomach, intestines and blood vessels, nervous heart conditions. Further acknowledgement as appetizer, headache relief, hysteria, epilepsy, tape worm, diarrhoea, lose stomach, fever. PA0 Externally: Vapour baths given to children will quieten and encourage restful sleep (Bello-Russ. Academy of Science, Minsk, 1965)." PA0 "Pleasant and warm-balsamic, slightly woody odor of good tenacity. The undiluted material shows some "pepperiness". PA0 This material, although commonly found in natural oils, has found only limited use in perfumery . . . "
Valerian oil is the essential oil obtained from the root of Valeriana officinalis. The folk medicine literature lists the valerian root (fresn or dried) as being useful as an antispasmodic, carminative, stomachic and sedative. It has been used to treat migraine, insomnia, hysteria, fatigue and stomach cramps that cause vomiting (A. Y. Leung, "Encyclopedia of Common Natural Ingredients", John Wiley & Sons, New York, N.Y., 1980, pages 317-320).
Regarding valerian oil's use in Russia, Hutchens, et al, "Indian Herbalogy of North America", (published by Merco of Windsor, Ontario, Canada), 5th edition, 1974, states:
In "Sedative Principles of Valeriana Roots", Hikino, et al, Shoyakugaku Zasshi, 34, (1), 1980, pages 19-24, it is indicated that compounds possessing sedative activity, isolated from valerian roots, have failed to fully account for the sedative activity exhibited by the roots per se. It is further stated therein that, recently, iridoids named valepotriates were isolated as analgesic and sedative principles from Indian valerian roots. In this paper, a correlation between the contents of the valepotriates and the pharmacological activity of various valerian roots was examined. Napalese and Chinese valerian roots containing an appreciable quantity of valepotriates showed no sedative activity, while Japanese valerian root containing less valepotriates inhibited stress-induced ulcer formation and prolonged hexobarbital-induced sleep in mice. An extract of "Hokkai-kisso", i.e., roots of a Japanese valerian, was fractionated and the effect of each of the fractions on the enhancement of hexobarbital anesthesis was tested. Kessyl glycol diacetate, Kessyl glycol 8-acetate and Kessyl glycol 2-acetate were obtained as active principles therefrom. The enhancement of hexobarbital anesthesis by Kessyl glycol diacetate was assumed to be due to its inhibitory effect on the central nervous system. Kessyl glycol diacetate exhibited no inhibitory action on the stress-induced ulcer production.
The chemical constituents, pharmacology and known uses of valerian are reviewed in: "Herbal Remedies Used in Sedative and Antirheumatic Preparations: Part I", Phillipson, et al, The Pharmaceutical Journal, July 21, 1984, pages 80-82.
Another potentially interesting plant substance is nutmeg which was important in medicine as well as well as in cooking. It was used as a therapeutic by Arab physicians as early as the 7th Century A.D. for treatment for disorders of the digestive system, kidney disease, pain and lymphatic ailments. Nutmeg is a significant item in the Hindu Pharmacopeia wherein it has been prescribed for fever, consumption, asthma and heart disease. Nutmeg is employed by folk practitioners in India as an analgesic and sedative. In large doses (two teaspoons or more of ground nutmeg), nutmeg exhibits mild hallucinogenic activity, the description by Payne (R. B. Payne, New England Journal of Medicine, 269, pages 36-38 [1963]) being illustrative of this activity. Two college students, 19 and 20 years old, each consumed two tablespoons (14 grams or the equivalent of two whole seeds) of powdered nutmeg in milk. About 5 hours later, each had the onset of a leaden feeling in the extremities and a nonchalant detached mental state described as "unreal" or "dreamlike". Rapid heart rates and palpitation were observed and both complained of dry mouth and thirst. See, also, Wiel (A. T. Weil, Ethnopharmacol. Search Psychoact. Drugs [Proc. Symp.], 1967, [Pub. 1979], 188-201).
The fraction of nutmeg responsible for the mild hallucinogenic activity is suggested by the literature to be the aromatic fraction of the oil containing safrole, methyleugenol, eugenol, methylisoeugenol, myristicin, elemicin, isoelemicin and methoxyeugenol as the major components. Of these, myristicin, elemicin and isoelemicin have been reported to be the active molecules (A. T. Shulgin, et al, Ethnopharmacol. Search Psychoact. Drugs [Proc. Symp.], 1967, [Pub. 1979], 202-214). The myristicin-elemicin fraction of oil of nutmeg produces many of the activities of crude ground nutmeg but lacks adequate potency to explain the nutmeg intoxication syndrome on a quantitative basis. Nutmeg and synthetically-made myristicin show a mild degree of monoamine oxidase inhibiting activity. The monoamine oxidase activity is found in the volatile component of nutmeg (E. B. Truitt, Jr., Ethnopharmacol. Search Psychoact. Drugs [Proc. Symp.], 1967, [Pub. 1979], 215-222).
Nutmeg oil, known as myristica fragrans, or myristicaceae,is the essential oil from the kernel of the fruit of the nutmeg tree. The stone of the fruit is enclosed within a husk which, when dried, is known as mace. "Mace Extract" is an aromatic essence extracted from mace. "Nutmeg Butter" is a fixed oil obtained by hot-pressing the nutmeg kernels, and contains myristine, butyrin, olein, palmitine and stearine. The essence contains 80% pinene and camphene, 8% dipentene, 6% terpenic alcohols, (linalool, borneol, terpineol and geraniol), 4% myristicin and various substances such as eugenol and safrol. Valnet, "The Practice of Aromatherapy", (supra) states that, for external use:
A form of nutmeg oil, Myristica castaneifolia (Myristacaceae) Fiji is described as possessing biological activity, specifically in the antitumor field, in U.S. Letters Pat. No. 4,352,797 issued on Oct. 5, 1982, the specification for which is incorporated by reference herein. At page 4 of the January/February 1984 (Vol 6, No. 1) edition of FOCUS (World Wildlife Fund-U.S.), nutmeg is indicated as being an analgesic and a hallucinogen. In the paper "Nutmeg as a Narcotic" by Kalbhen in Angew. Chem. 83, 379 (1971), Kalbhen discloses that the hallucinogenic ingredients of nutmeg include, interalia,:
The Kalbhen paper is incorporated herein by reference.
Furthermore, Myristica fragrans is disclosed at Chem. Abstracts, Vol. 101, No. 2831g (abstract of Japan Kokai Tokkyo Koho 59/55,827) as being useful in the field of drug stabilization in conjunction with the utilization of transdermal pharmaceuticals. The said abstract and the said Japanese Kokai Tokkyo Koho are incorporated herein by reference.
Furthermore, isoelemicin having the structure: ##STR4## is a known flavor ingredient as set forth in U.S. Letters Pat. No. 3,686,004 issued on Aug. 22, 1972, the soecification for which is incorporated by reference herein. By the same token, myristicin having the structure: ##STR5## is disclosed as a component of the aroma of blueberries in J. Sci. Food Agric., 1983, 34(9), 992-6 (abstracted at Chem. Abstracts, Vol. 99:174466r). (Hirvi, et al) (Copy of paper incorporated by reference herein).
Furthermore, regarding myristicin, Arctander, "Perfume & Flavor Chemicals (Aroma Chemicals)", published by the author in 1969, states at monograph 2291, that myristicin is:
The essential oils described above are also common perfumery ingredients as described in Arctander, "Perfume and Flavors Materials of Natural Origin", published by the author in 1960. (Mace extract at columns 391-393; neroli oil at columns 435-437; nutmeg oil at columns 442-445; and valerian oil at columns 637-638).
In summary, the materials employed in the practice of this invention, are known in the art and are known to exhibit physiologic activity. However, insofar as the inventors hereof have been able to ascertain, no suggestion relevant to reducing physiological and/or subjective reactivity to stress is made in the prior art.